RNA Molecule FGF21 May Be Therapeutic Target

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by Marta Figueiredo PhD |

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The blood levels of a signaling molecule called fibroblast growth factor 21 (FGF21) are significantly reduced in people with high-altitude pulmonary hypertension (PH) and in mice with hypoxia-induced PH, a study shows.

Hypoxia refers to low oxygen conditions and chronic hypoxia is a common cause of PH.

Also, treatment with FGF21 was found to ease hypoxia-induced PH in mice by increasing the levels of a long non-coding RNA (lncRNA) molecule called H19 in pulmonary artery smooth muscle cells (PASMCs), which are the cells that line the walls of pulmonary arteries and are overgrown in PH.

H19 was shown to suppress the cell growth-promoting mTORC1 signaling pathway.

These findings shed light on the underlying mechanisms of FGF21’s previously reported beneficial effects in PH mouse models, further supporting its therapeutic potential in PH and pinpointing H19 and mTORC1 signaling as new targets, the researchers noted.

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The study, “FGF21 alleviates pulmonary hypertension by inhibiting mTORC1/EIF4EBP1 pathway via H19,” was published in the Journal of Cellular and Molecular Medicine.

PH is characterized by progressive narrowing of pulmonary arteries, restricting blood and oxygen flow and raising blood pressure (hypertension). This arterial narrowing is the result of progressive blood vessel contraction and remodeling, a process that involves the uncontrolled growth of PASMCs, progressively thickening the arterial walls.

In a prior study, a team of researchers in China showed that treatment with FGF21 — a signaling molecule with protecting effects in blood vessels — lessened hypoxia-induced PH in rats.

Now, the same team set out to unravel the mechanisms behind FGF21’s beneficial effects in PH by looking at potential lncRNA targets. These RNA molecules can regulate gene activity, and several lncRNAs, such as MEG3 and MANTIS, have been shown to “play a key role in the occurrence and development of PH,” the researchers wrote.

The team first found that FGF21 levels in the blood were reduced significantly in both mice with hypoxia-induced PH and in people with high-altitude PH relative to their healthy counterparts, further supporting a role for FGF21 in PH. In addition, treating these mice with FGF21 partially prevented the development of PH, while FGF21 deficiency resulted in worsened PH.

Then they analyzed the levels of 171 lncRNAs in lung tissue of healthy mice and hypoxia-induced PH mice treated (or not) with FGF21. Results showed that among the 10 lcnRNAs with the most significant changes upon FGF21 treatment, H19 was the most abundantly produced.

H19 levels were reduced in mice exposed to hypoxia and significantly increased with FGF21 treatment. H19 “has been reported to be a multifunctional lncRNA that regulates cell growth,” suggesting it may play a cell growth-suppressing role in PH, the team wrote.

Indeed, further analyses showed that FGF21 treatment raised H19 levels in PASMCs in a dose-dependent manner and that these increased levels suppressed PASMCs’ growth.

In addition, FGF21 and H19’s effects were found to involve the suppression of the mTORC1 pathway, which is known to promote cell growth. This was associated, at least in part, with H19’s binding to and suppression of the EIF4EBP1 gene, one of the pathway’s major effectors.

These findings highlight that FGF21 partially reduces hypoxia-induced PH and its associated uncontrolled growth of PASMC through H19, which suppresses the mTORC1/EIF4EBP1 signaling pathway.

The data suggests that “FGF21 and H19 could serve as potential targets for the development of a therapy for PH,” the researchers wrote.

More studies are needed to better understand the effects of these molecules in PH and confirm their potential as therapeutic approaches and/or targets.